Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
In response to vascular injury such as a cut, coagulation enzymes are activated in a stepwise manner, ultimately resulting in the formation of a blood clot at the site of injury. Thrombin is generated from its inactive precursor prothrombin in the final step of this cascade and subsequently produces the fibrous clot. Prothrombinase, the enzyme complex that activates thrombin, consists of the protease Factor Xa (FXa) and its non-enzymatic cofactor, activated Factor V (FVa), which assemble on phospholipid membrane surfaces near the injury. FVa is critical for thrombin generation, as FXa has very little activity in the absence of FVa. Like other proteins of the coagulation cascade, the active cofactor FVa is generated from an inactive precursor, Factor V (FV) which is an inactive procofactor. FV activation occurs by removal of a large inhibitory “B” domain as two fragments (˜71 kDa and ˜150 kDa) that maintains FV in an inactive state. Accordingly, the inhibition of FV activation or stabilization of the inactive procofactor state is desired in order to reduce improper or unwanted thrombin generation and clot formation.